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The mechano-chemistry of a viral genome packaging motor 病毒基因组包装马达的机械化学原理
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-04 DOI: 10.1016/j.sbi.2024.102945
Double-stranded DNA viruses actively package their genomes into pre-assembled protein capsids using energy derived from virus-encoded ASCE ATPase ring motors. Single molecule experiments in the aughts and early 2010s demonstrated that these motors are some of the most powerful molecular motors in nature, and that the activities of individual subunits around the ATPase ring motor are highly coordinated to ensure efficient genome encapsidation. While these studies provided a comprehensive kinetic scheme describing the events that occur during packaging, the physical basis of force generation and subunit coordination remained elusive. This article reviews recent structural and computational results that have begun to illuminate the molecular basis of force generation and DNA translocation in these powerful molecular motors.
双链DNA病毒利用病毒编码的ASCE ATPase环马达产生的能量,积极地将其基因组包装到预先组装好的蛋白囊壳中。二十世纪八十年代和二十一世纪初的单分子实验证明,这些马达是自然界中一些最强大的分子马达,ATPase 环马达周围各个亚基的活动高度协调,以确保高效的基因组封装。虽然这些研究提供了一个全面的动力学方案来描述包装过程中发生的事件,但力的产生和亚基协调的物理基础仍然难以捉摸。本文回顾了最近的结构和计算成果,这些成果已开始阐明这些强大分子马达产生作用力和 DNA 转位的分子基础。
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引用次数: 0
Characterizing protein-protein interactions with thermal proteome profiling 利用热蛋白质组图谱鉴定蛋白质与蛋白质之间的相互作用
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-30 DOI: 10.1016/j.sbi.2024.102946
Thermal proteome profiling (TPP) is an innovative technique that uses the principle of protein thermal stability to identify potential protein interaction partners. Employing quantitative mass spectrometry, TPP measures protein stability across the proteome, offering a comprehensive snapshot of protein interactions in a single experiment. When studying protein-protein interactions (PPI), TPP leverages changes in apparent protein melting temperatures to identify transient and weak interactions that most traditional PPI detection methodologies struggle to measure. This review discusses current TPP methodologies, the challenges of interpreting the resulting complex datasets, and opportunities to deepen and improve PPI networks. By advancing our grasp of intricate protein interactions, TPP promises to illuminate the molecular basis of diseases and drive the discovery of novel therapeutic targets.
热蛋白质组分析(TPP)是一项创新技术,它利用蛋白质热稳定性原理来识别潜在的蛋白质相互作用伙伴。TPP 采用定量质谱法测量整个蛋白质组的蛋白质稳定性,在一次实验中提供蛋白质相互作用的全面快照。在研究蛋白质-蛋白质相互作用(PPI)时,TPP 利用表观蛋白质熔解温度的变化来识别大多数传统 PPI 检测方法难以测量的瞬时弱相互作用。本综述讨论了当前的 TPP 方法、解读由此产生的复杂数据集所面临的挑战以及深化和改进 PPI 网络的机会。通过推进我们对错综复杂的蛋白质相互作用的掌握,TPP有望阐明疾病的分子基础并推动新型治疗靶点的发现。
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引用次数: 0
Retraction notice to “Liquid-EM goes viral – visualizing structure and dynamics” [Curr Opin Struct Biol 75 (August 2022) 102426] 液体电子显微镜(Liquid-EM)病毒式传播--结构与动力学可视化》撤稿通知 [Curr Opin Struct Biol 75 (August 2022) 102426]
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-28 DOI: 10.1016/j.sbi.2024.102947
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引用次数: 0
Non-canonical amino acids for site-directed spin labeling of membrane proteins 用于膜蛋白定点自旋标记的非典型氨基酸。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-24 DOI: 10.1016/j.sbi.2024.102936
Membrane proteins remain challenging targets for conventional structural biology techniques because they need to reside within complex hydrophobic lipid environments to maintain proper structure and function. Magnetic resonance combined with site-directed spin labeling is an alternative method that provides atomic-level structural and dynamical information from effects introduced by an electron- or nuclear-based spin label. With the advent of bioorthogonal click chemistries and genetically engineered non-canonical amino acids (ncAAs), options for linking spin probes to biomolecules have substantially broadened outside the conventional cysteine-based labeling scheme. Here, we highlight current strategies to spin-label membrane proteins through ncAAs for nuclear and electron paramagnetic resonance applications. Such advances are critical for developing bioorthogonal spin labeling schemes to achieve in-cell labeling and in-cell measurements of membrane protein conformational dynamics.
膜蛋白仍然是传统结构生物学技术的挑战目标,因为它们需要在复杂的疏水性脂质环境中才能保持适当的结构和功能。磁共振与位点定向自旋标记相结合是一种替代方法,可通过电子或核基自旋标记引入的效应提供原子级结构和动态信息。随着生物正交点击化学和基因工程非典型氨基酸(ncAAs)的出现,将自旋探针与生物大分子连接的选择范围大大拓宽,不再局限于传统的基于半胱氨酸的标记方案。在此,我们将重点介绍目前通过 ncAAs 对膜蛋白进行自旋标记以应用于核磁共振和电子顺磁共振的策略。这些进展对于开发生物正交自旋标记方案以实现细胞内标记和细胞内膜蛋白构象动态测量至关重要。
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引用次数: 0
Empowering the molecular ruler techniques with unnatural base pair system to explore conformational dynamics of flaviviral RNAs 利用非天然碱基配对系统增强分子尺技术,探索黄病毒 RNA 的构象动力学。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-22 DOI: 10.1016/j.sbi.2024.102944
RNA's inherent flexibility and dynamics pose great challenges to characterize its structure and dynamics using conventional techniques including X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy and cryo-electron microscopy. Three complementary molecular ruler techniques, the electron paramagnetic resonance (EPR) spectroscopy, X-ray scattering interferometry (XSI) and Förster resonance energy transfer (FRET) which measure intramolecular and intermolecular pair-wise distance distributions in the nanometer range in a solution, have become increasingly popular and been widely used to explore RNA structure and dynamics. The prerequisites for successful application of such techniques are to achieve site-specific labeling of RNAs with spin labels, fluorescent tags, or gold nanoparticles, respectively, which are however, challenging, especially to large RNAs (generally >200 nts). Here, we briefly review the basics of these molecular rulers, how the NaM-TPT3 unnatural base pair system empower them, and their applications to explore conformational dynamics of large RNAs, especially in the context of flavivirus RNA genome.
RNA 固有的灵活性和动态性给使用传统技术(包括 X 射线晶体学、核磁共振(NMR)光谱和冷冻电镜)描述其结构和动态带来了巨大挑战。电子顺磁共振(EPR)光谱法、X 射线散射干涉测量法(XSI)和佛斯特共振能量转移法(FRET)这三种互补的分子尺技术可以测量溶液中纳米范围内的分子内和分子间配对距离分布,它们在探索 RNA 结构和动力学方面越来越受欢迎并得到广泛应用。成功应用此类技术的前提条件是分别用自旋标签、荧光标签或金纳米粒子对 RNA 进行位点特异性标记,但这具有挑战性,尤其是对大型 RNA(一般大于 200 nts)而言。在此,我们简要回顾了这些分子标尺的基本原理、NaM-TPT3 非自然碱基对系统如何赋予它们权力,以及它们在探索大型 RNA 构象动力学方面的应用,尤其是在黄病毒 RNA 基因组方面的应用。
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引用次数: 0
Editorial overview: Cryo-electron microscopy 编辑综述:冷冻电镜。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-19 DOI: 10.1016/j.sbi.2024.102937
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引用次数: 0
Fuzzy protein-DNA interactions and beyond: A common theme in transcription? 模糊的蛋白质-DNA相互作用及其他:转录的共同主题?
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-17 DOI: 10.1016/j.sbi.2024.102941
Gene expression regulation requires both diversity and specificity. How can these two contradictory conditions be reconciled? Dynamic DNA recognition mechanisms lead to heterogeneous bound conformations, which can be shifted by the cellular cues. Here we summarise recent experimental evidence on how fuzzy interactions contribute to chromatin remodelling, regulation of DNA replication and repair and transcription factor binding. We describe how the binding mode continuum between DNA and regulatory factors lead to variable, multisite contact patterns; polyelectrolyte competitions; on-the-fly shape readouts; autoinhibition controlled by posttranslational modifications or dynamic oligomerisation mechanisms. Increasing experimental evidence supports the rugged energy landscape of the bound protein-DNA assembly, modulation of which leads to distinct functional outcomes. Recent results suggest the evolutionary conservation of these combinatorial mechanisms with moderate sequence constraints in the malleable transcriptional machinery.
基因表达调控既需要多样性,也需要特异性。如何协调这两个相互矛盾的条件?动态的 DNA 识别机制会导致异质的结合构象,而这些构象会因细胞线索而改变。在此,我们总结了最近的实验证据,说明模糊相互作用如何有助于染色质重塑、DNA 复制和修复调控以及转录因子结合。我们描述了 DNA 与调控因子之间的结合模式连续性如何导致可变的多位点接触模式、多电解质竞争、即时形状读数、由翻译后修饰或动态寡聚机制控制的自动抑制。越来越多的实验证据支持结合蛋白质-DNA 组装的崎岖能量景观,对其进行调节可导致不同的功能结果。最近的研究结果表明,这些组合机制在进化过程中保持了可塑性转录机制中适度的序列限制。
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引用次数: 0
Extracellular DNA-protein interactions 细胞外 DNA 蛋白相互作用
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-16 DOI: 10.1016/j.sbi.2024.102943
Intracellular DNA primarily serves as the cellular genetic material both in eukaryotes and prokaryotes. This function is often regulated by alterations in the DNA structure to accommodate transcription, recombination, and DNA replication. Extracellularly, both eukaryotic and prokaryotic cells take advantage of DNA plenty in addition to a permissive environment and create novel structures to fulfill multiple new roles. As often occurs intracellularly, extracellular DNA requires proteins to facilitate and stabilize these important structures. Here I review, both host and eubacterial nucleoprotein structures, their composition, their functions, and how these distinct structures can interact. Even at this early stage of study, it is clear that extracellular chromatin plays important biological roles in the survival of both prokaryotic and eukaryotic organisms.
细胞内 DNA 主要是真核生物和原核生物的细胞遗传物质。这一功能通常由 DNA 结构的改变来调节,以适应转录、重组和 DNA 复制。在细胞外,无论是真核细胞还是原核细胞,都会利用大量的 DNA 和有利的环境,创造新的结构来发挥多种新的作用。与细胞内的情况一样,细胞外 DNA 也需要蛋白质来促进和稳定这些重要结构。在这里,我将回顾宿主和真细菌的核蛋白结构、它们的组成、它们的功能以及这些不同的结构如何相互作用。即使是在研究的早期阶段,细胞外染色质在原核生物和真核生物的生存过程中显然都发挥着重要的生物学作用。
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引用次数: 0
Nexus between RNA conformational dynamics and functional versatility RNA 构象动力学与功能多样性之间的联系
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-15 DOI: 10.1016/j.sbi.2024.102942
RNA conformational dynamics is pivotal for functional regulations in biology. RNA can function as versatile as protein but adopts multiple distinct structures. In this review, we provide a focused review of the recent advances in studies of RNA conformational dynamics and address some of the misconceptions about RNA structure and its conformational dynamics. We discuss why the traditional methods for structure determination come up short in describing RNA conformational space. The examples discussed provide illustrations of the structure-based mechanisms of RNAs with diverse roles, including viral, long noncoding, and catalytic RNAs, one of which focuses on the debated area of conformational heterogeneity of an RNA structural element in the HIV-1 genome.
RNA 的构象动力学对生物学中的功能调控至关重要。RNA 的功能与蛋白质一样多变,但却具有多种不同的结构。在这篇综述中,我们重点回顾了 RNA 构象动力学研究的最新进展,并探讨了有关 RNA 结构及其构象动力学的一些误解。我们讨论了为什么传统的结构测定方法无法描述 RNA 的构象空间。所讨论的例子说明了具有不同作用的 RNA(包括病毒 RNA、长非编码 RNA 和催化 RNA)基于结构的机制,其中一个例子重点讨论了 HIV-1 基因组中一个 RNA 结构单元的构象异质性这一有争议的领域。
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引用次数: 0
RNA ensembles from in vitro to in vivo: Toward predictive models of RNA cellular function 从体外到体内的 RNA 组合:建立 RNA 细胞功能预测模型
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-13 DOI: 10.1016/j.sbi.2024.102915
Deepening our understanding of RNA biology and accelerating development of RNA-based therapeutics go hand-in-hand—both requiring a transition from qualitative descriptions of RNA structure to quantitative models capable of predicting RNA behaviors, and from a static to an ensemble view. Ensembles are determined from their free energy landscapes, which define the relative populations of conformational states and the energetic barriers separating them. Experimental determination of RNA ensembles over the past decade has led to powerful predictive models of RNA behavior in vitro. It has also been shown during this time that the cellular environment redistributes RNA ensembles, changing the abundances of functionally relevant conformers relative to in vitro contexts with subsequent functional RNA consequences. However, recent studies have demonstrated that testing models built from in vitro ensembles with highly quantitative measurements of RNA cellular function, aided by emerging computational methodologies, enables predictive modelling of cellular activity and biological discovery.
加深我们对 RNA 生物学的理解和加速开发基于 RNA 的疗法是相辅相成的,两者都需要从 RNA 结构的定性描述过渡到能够预测 RNA 行为的定量模型,并从静态视角过渡到集合视角。组合是根据其自由能谱确定的,自由能谱定义了构象状态的相对数量以及将它们分开的能量障碍。在过去十年中,通过对 RNA 组合的实验测定,建立了强大的体外 RNA 行为预测模型。研究还表明,细胞环境重新分配了 RNA 组合,改变了与体外环境相关的功能构象的丰度,从而对 RNA 的功能产生了影响。然而,最近的研究表明,在新兴计算方法的帮助下,利用对 RNA 细胞功能的高度定量测量来测试根据体外组合建立的模型,可以对细胞活动和生物发现进行预测建模。
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Current opinion in structural biology
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